Circulating tumor DNA (ctDNA) and serum thymidine kinase 1 activity (TKa) matched dynamics in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor 2–negative (HER2-) advanced breast cancer (ABC) treated in first-line (1L) with ribociclib (RIB) and letrozole (LET) in the BioItaLEE trial.
Authors: Grazia Arpino, Giampaolo Bianchini, Luca Malorni, Alberto Zambelli, Fabio Puglisi, Lucia Del Mastro, Marco Colleoni, Filippo Montemurro, Giulia Valeria Bianchi, Ida Paris, Giacomo Allegrini, Stefano Tamberi, Marina Elena Cazzaniga, Michele Orditura, Claudio Zamagni, Donatella Grasso, Matteo Benelli, Maurizio Callari, Antonina Benfante, Michelino De Laurentiis
Journal: Journal of Clinical Oncology (2022)

1012 Background: Independent early dynamic assessment (baseline [D0] and day 15 of first cycle [D15]) of both TKa and ctDNA was prognostic and predictive in pts with HR+, HER2− ABC treated with RIB+LET enrolled in the BioItaLEE trial (NCT03439046). Here we performed a combined analysis of these two biomarkers. Methods: 287 pts were enrolled in the study. Overall, early dynamics were assessable for both biomarkers in 241/287 pts (84.0%). Methods applied for ctDNA and TKa evaluation were previously reported. For ctDNA, samples were defined as wild type (WT) if no mutations were observed at D0 and D15, ctDNA positive (+) if with or negative (-) if without a primary target mutation at D15. Samples were TKa+ or TKa- if TKa levels were above or below the limit of detection at D15. According to ctDNA and TKa pts were classified as: WT/TKa-, WT/TKa+, ctDNA-/TKa-, ctDNA-/TKa+, ctDNA+/TKa- and ctDNA+/TKa+ and then divided into 3 main study groups (GRs) WT/TKa- (GR1, n = 126), WT/TKa+, ctDNA-/TKa-, ctDNA-/TKa+, ctDNA+/TKa- (GR2, n = 96) and ctDNA+/TKa+ (GR3, n = 19). The association between biomarkers and PFS (progression-free survival) was estimated using Kaplan-Meier analysis and multivariate Cox models with 95% confidence intervals (CIs) adjusted for clinical variables. Results: Median follow-up was 26.9 months. In multivariate Cox models both TKa dynamics and mutational tumor burden at D15 were independently predictive of PFS. Hazard ratios (HRs) were 0.37 (95% CI: 0.23-0.60; p &lt; 0.0001) for WT vs ctDNA+ and 0.56 (95% CI: 0.32-1.00; p = 0.0506) for ctDNA- vs ctDNA+. For TKa, HR was 0.49 (95% CI: 0.30-0.80; p = 0.0040) in TKa- vs TKa+. Interestingly combining the two variables further improve prediction of outcome. HRs for TKa- vs TKa+ were 0.17 (95% CI: 0.09-0.32; p &lt; 0.0001), 0.28 (95% CI: 0.13-0.59; p = 0.0009) and 0.44 (95% CI: 0.23-0.86; p = 0.0169) in WT, ctDNA- and ctDNA+ pts, respectively. Considering the 3 study GRs, median PFSs (95% CI) were not reached (27.89, NE), 19.58 (13.83, 23.39) and 6.65 (2.83, 12.16) months in GR1, GR2 and GR3, respectively, p &lt; 0.001. At multivariate Cox models, HRs of GR1 and GR2 compared with GR3 were 0.17 (95% CI: 0.09-0.32; p &lt; 0.0001) and 0.37 (95% CI: 0.20-0.67; p = 0.001) respectively. Conclusions: These findings suggest that combining the early dynamic assessment of both ctDNA and TKa may improve outcome prediction in pts treated with RIB+LET. Pts with ctDNA+/TKa+ are strongly enriched for non-responders. TKa and ctDNA capture different features of tumor biological activity and their combination warrants further evaluation in relation to other treatments, settings, and diseases. Clinical trial information: NCT03439046.